Many etiologies lead to the development of dilated cardiomyopathy. Idiopathic dilated cardiomyopathy arises from intrinsic muscle disease in the presence of normal coronary arteries and the absence of a clear toxic or immunologic insult. Approximately 30 percent of idiopathic dilated cardiomyopathy patients have first degree relatives that also show evidence of cardiac dilatation with or without symptoms of congestive heart failure. Supporting this, genetic loci have been significantly associated with familial dilated cardiomyopathy (FDC). Positional cloning efforts are underway to increase our understanding of the molecular mechanisms that underlie familial dilated cardiomyopathy. Through genetic linkage analysis, we have identified a region of chromosome 6q23 that is associated with dilated cardiomyopathy, conduction system disease that produces progressive atrio-ventricular block and a mild, adult onset, slowly progressive muscular dystrophy. We have constructed a physical map of this region of chromosome 6 and evaluation of candidate genes is underway. We have also discovered a second region, chromosome 2q22, that is associated with dilated cardiomyopathy and ventricular arrhythmias. We propose to refine the genetic interval, identify candidate genes and, through mutation analysis, identify the gene responsible for chromosome 2-associated FDC. The FDC-gene product will be studied for expression patterns in both normal and diseased tissue. The murine homolog of the FDC-gene will be determined. We will also establish a clinical and DNA database of dilated cardiomyopathy patients. This database will be used to determine the role of certain mutations in the development of the cardiomyopathic process. While genetic heterogeneity is present in FDC, the study of genes responsible for this disorder will reveal whether multiple cellular mechanism lead to cardiomyopathy. Additionally, in families with dilated cardiomyopathy, we find a prodrome of arrhythmias prior to the onset of cardiac dilatation and congestive heart failure. By developing genetic markers, we will identify those at risk for arrhythmia and most like to benefit from pacemaker and/or implantable defibrillator treatment.